Theophylline, also known as 1,3-dimethylxanthine, is a bitter tasting white powder, slightly soluble in water, of the formula ##STR3##
It has a bronchodilating action due to a relaxation of the bronchial smooth muscles; it is active toward all bronchoconstrictive agents. It also has an inhibiting action on mastocytes by partially inhibiting their degranulation with the release of histamine in hypersensitivity reactions.
As R. W. Butcher and E. W. Sutherland, J. Biol. Chem., vol. 237, pp 1244-1250 (1962) showed, this activity seems linked to a competitive inhibition on the phosphodiesterase, an enzyme that catalyzes the transformation of cyclic AMP (cyclic adenosine 3',5'-monophosphate) into 5'-AMP. It results in a tissue increase of cyclic AMP which would be responsible for the activity of the theophylline.
Theophylline has been used for a long time in treating asthma, but its early use had suffered some discredit, the product being considered poorly tolerated and ineffective. New determination techniques by high-performance liquid chromatography and by immunoenzymological methods now permit a simple and exact determination of theophylline blood levels. These methods have brought about progress in the use of the medicine and theophylline is now beginning to take an important place in treating asthma. Although the use of adrenocorticosteroids may be necessary at times in treating the asthma, bronchodilating medicines hold a dominant place in the therapy and theophylline is undoubtedly the most useful of these bronchodilating medicines.
Theophylline is absorbed very well orally. On the other hand, rectal absorption is very irregular. Intrapulmonary administration by aerosol is ineffective.
An effect-blood concentration relation has been established. For a blood level between 5 and 20 mg/l, improvement of the pulmonary vital capacity is proportional to the logarithm of the concentration. Above a 20 mg/l concentration, intolerance signs can appear: digestive disorders, nervous troubles, cardiac troubles, then neurological symptoms.
Most of the theophylline is metabolized at the hepatic level to give inactive metabolites eliminated by the kidneys. The half-life can vary with age and the individuals; on the average, it is close to 6 hours in a normal adult, but half-lives of 4 hours are not uncommon.
For good results, the patients must absorb a dose of medicine every 6 hours. However, since asthma takes on a chronic nature, it is hardly possible to achieve carefully followed treatment with such frequent doses regularly space over the day.
Accordingly, various galenical formulas have been proposed, for example of the microgranule type, from which theophylline is slowly released in the digestive tract.
However, it is desirable to obtain more lasting blood levels, which would make it possible to simplify the dosage, by reducing the number of doses of medicine taken and also by reducing the fluctuations of the blood level.